Ischemic Acute Tubular Necrosis Research Articles

The role of peritoneal dialysis in the treatment of acute kidney injury in neurocritical patients: a retrospective Brazilian study.

Acute kidney injury (AKI) occurs frequently in the neurocritical intensive care unit and is associated with greater morbidity and mortality. AKI and its treatment, including acute kidney replacement therapy, can expose patients to a secondary greater brain injury. This study aimed to explore the role of peritoneal dialysis (PD) in neurocritical AKI patients in relation to metabolic and fluid control, complications related to PD and outcome. Neurocritical AKI patients were treated by PD (prescribed Kt/V = 0.40/session) using a flexible catheter and a cycler and lactate as a buffer. A total of 58 patients were included. The mean age was 61.8 ± 13.2 years, 65.5% were in the intensive care unit, 68.5% needed intravenous inotropic agents, 72.4% were on mechanical ventilation, APACHE II was 16 ± 6.67 and the main neurological diagnoses were stroke (25.9%) and intracerebral haemorrhage (31%). Ischaemic acute tubular necrosis (iATN) was the most common cause of AKI (51.7%), followed by nephrotoxic ATN AKI (25.8%). The main dialysis indications were uraemia and hypervolemia. Blood urea and creatinine levels stabilised after four sessions at around 48 ± 11 mg/dL and 2.9 ± 0.4 mg/dL, respectively. Negative fluid balance and ultrafiltration increased progressively and stabilised around 2.1 ± 0.4 L /day. Weekly delivered Kt/V was 2.6 ± 0.31. The median number of high-volume PD sessions was 6 (4-10). Peritonitis and mechanical complications were not frequent (8.6% and 10.3%, respectively). Mortality rate was 58.6%. Logistic regression identified as factors associated with death in neurocritical AKI patients: age (odds ratio (OR) = 1.14, 95% confidence interval (CI) = 1.09-2.16, p = 0.001), nephrotoxic AKI (OR = 0.78, 95% CI = 0.69- 0.95, p = 0.03), mechanical ventilation (OR = 1.54, 95% CI = 1.17-2.46, p = 0.01), intracerebral haemorrhage as main neurological diagnoses (OR = 1.15, 95% CI = 1.09-2.11, p = 0.03) and negative fluid balance after two PD sessions (OR = 0.94, 95% CI = 0.74-0.97, p = 0.009). Our study suggests that careful prescription may contribute to providing adequate treatment for most neurocritical AKI patients without contraindications for PD use, allowing adequate metabolic and fluid control, with no increase in the number of infectious, mechanical and metabolic complications. Mechanical ventilation, positive fluid balance and intracerebral haemorrhage were factors associated with mortality, while patients with nephrotoxic AKI had lower odds of mortality compared to those with septic and ischaemic AKI. Further studies are needed to investigate better the role of PD in neurocritical patients with AKI.

ACUTE KIDNEY INJURY AS A PREDICTOR OF MORTALITY IN PATIENTS WITH COVID-19

ACUTE KIDNEY INJURY AS A PREDICTOR OF MORTALITY IN PATIENTS WITH COVID-19

A HARD PILL TO SWALLOW

A HARD PILL TO SWALLOW

Lipopolysaccharide Pretreatment Prevents Medullary Vascular Congestion following Renal Ischemia by Limiting Early Reperfusion of the Medullary Circulation.

Vascular congestion of the renal medulla-trapped red blood cells in the medullary microvasculature-is a hallmark finding at autopsy in patients with ischemic acute tubular necrosis. Despite this, the pathogenesis of vascular congestion is not well defined. In this study, to investigate the pathogenesis of vascular congestion and its role in promoting renal injury, we assessed renal vascular congestion and tubular injury after ischemia reperfusion in rats pretreated with low-dose LPS or saline (control). We used laser Doppler flowmetry to determine whether pretreatment with low-dose LPS prevented vascular congestion by altering renal hemodynamics during reperfusion. We found that vascular congestion originated during the ischemic period in the renal venous circulation. In control animals, the return of blood flow was followed by the development of congestion in the capillary plexus of the outer medulla and severe tubular injury early in reperfusion. Laser Doppler flowmetry indicated that blood flow returned rapidly to the medulla, several minutes before recovery of full cortical perfusion. In contrast, LPS pretreatment prevented both the formation of medullary congestion and its associated tubular injury. Laser Doppler flowmetry in LPS-pretreated rats suggested that limiting early reperfusion of the medulla facilitated this protective effect, because it allowed cortical perfusion to recover and clear congestion from the large cortical veins, which also drain the medulla. Blockage of the renal venous vessels and a mismatch in the timing of cortical and medullary reperfusion results in congestion of the outer medulla's capillary plexus and promotes early tubular injury after renal ischemia. These findings indicate that hemodynamics during reperfusion contribute to the renal medulla's susceptibility to ischemic injury.

Acute kidney injury secondary to obstetric complications in the third trimester of pregnancy and the puerperium

Background Acute kidney injury (AKI) in pregnancy is still a frequent health problem in developing countries. The aim of our study is to assess the prevalence and outcome of AKI secondary to obstetric complications during the third trimester of pregnancy and the puerperium Patients and methods A retrospective study conducted on 80 patients presented with AKI secondary to obstetric complications during the third trimester of pregnancy and the puerperium. All patients were recruited from the National Institute of Nephrology and Urology in Cairo during the period from June 2014 to June 2016. Data was collected from the unit database and patient medical charts including patient's history and examination findings during admission, laboratory parameters on admission including complete blood count and routine chemistry, hospital course, treatment received including renal replacement therapy and maternal and fetal outcomes. Results Our observational study included 80 patients presented with AKI during late pregnancy and the puerperium. Mean maternal age was 32±6 years and mean gestational age at presentation was 27±9 weeks. Mean serum creatinine was 7.7±2.4 mg/dl. Most of the patients who developed AKI did not receive antenatal care 67.5% (n=54). Also, more than half of the patients had a previous history of preeclampsia 52.5% (n=42). The median duration of hospital stay was 13 (6–51 interquartile range) days. Five (6%) patients underwent renal biopsy; 55 (69%) patients received hemodialysis as a renal replacement therapy while five patients received plasma exchange. The main etiology of AKI in our study was ischemic acute tubular necrosis 50% (n=40). Five (8%) patients developed chronic kidney disease and three patients (4%) progressed to end-stage renal disease. Maternal mortality was 4% (n=3) and fetal mortality was 74% (59 fetus). Conclusion AKI in late pregnancy and puerperium still presents as a health problem in developing countries. Most patients with AKI had a history of preeclampsia. Also, most of them had not received proper antenatal care. Improvement of the antenatal care is crucial for early detection and prevention of such problems.

Acute Kidney Injury in the Modern Era of Allogeneic Hematopoietic Stem Cell Transplantation.

AKI is a major complication of allogeneic hematopoietic stem cell transplantation, increasing risk of nonrelapse mortality. AKI etiology is often ambiguous due to heterogeneity of conditioning/graft versus host disease regimens. To date, graft versus host disease and calcineurin inhibitor effects on AKI are not well defined. We aimed to describe AKI and assess pre-/post-hematopoietic transplant risk factors in a large recent cohort. We performed a single-center, retrospective study of 616 allogeneic hematopoietic cell transplant recipients from 2014 to 2017. We defined AKI and CKD based on Kidney Disease Improving Global Outcomes (KDIGO) criteria and estimated GFR using the Chronic Kidney Disease Epidemiology Collaboration equation. We assessed AKI pre-/post-hematopoietic transplant risk factors using cause-specific Cox regression and association of AKI with CKD outcomes using chi-squared test. AKI was treated as a time-dependent variable in relation to nonrelapse mortality. Incidence of AKI by day 100 was 64%. Exposure to tacrolimus and other nephrotoxins conferred a higher risk of AKI, but tacrolimus levels were not associated with severity. Reduced-intensity conditioning carried higher AKI risk compared with myeloablative conditioning. Most stage 3 AKIs were due to ischemic acute tubular necrosis and calcineurin inhibitor nephrotoxicity. KRT was initiated in 21 out of 616 patients (3%); of these 21 patients, nine (43%) recovered and five (24%) survived to hospital discharge. T cell-depleted transplants, higher baseline serum albumin, and non-Hispanic ethnicity were associated with lower risk of AKI. CKD developed in 21% (73 of 345) of patients after 12 months. Nonrelapse mortality was higher in those with AKI (hazard ratio, 2.77; 95% confidence interval, 1.8 to 4.27). AKI post-hematopoietic cell transplant remains a major concern. Risk of AKI was higher with exposure to calcineurin inhibitors. T cell-depleted hematopoietic cell transplants and higher serum albumin had lower risk of AKI. Of the patients requiring KRT, 43% recovered kidney function. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_09_07_CJN19801220.mp3.

Histopathologic and Ultrastructural Findings in Postmortem Kidney Biopsy Material in 12 Patients with AKI and COVID-19.

Histopathologic and Ultrastructural Findings in Postmortem Kidney Biopsy Material in 12 Patients with AKI and COVID-19.

A prospective study of clinical characteristics and outcomes of acute kidney injury in a tertiary care Centre

BackgroundAcute kidney injury (AKI) is a major global health problem. We aim to evaluate the epidemiology, risk factors and outcomes of AKI episodes in our single centre.MethodologyWe prospectively identified 422 AKI and acute on chronic kidney disease episodes in 404 patients meeting KDIGO definitions using electronic medical records and clinical data from 15th July to 22nd October 2016, excluding patients with baseline estimated GFR (eGFR) of < 15 mL/min. Patients were followed up till 6 months after AKI diagnosis.ResultsThe mean age was 65.8 ± 14.1. Majority of patients were male (58.2%) of Chinese ethnicity (68.8%). One hundred and thirty-two patients (32.6%) were diagnosed in acute care units. Seventy-five percent of patients developed AKI during admission in a non-Renal specialty. Mean baseline eGFR was 50.2 ± 27.7 mL/min. Mean creatinine at AKI diagnosis was 297 ± 161 μmol/L. Renal consultations were initiated at KDIGO Stages 1, 2 and 3 in 58.9, 24.5 and 16.6% of patients, respectively. Three hundred and ten (76.7%) patients had a single etiology of AKI with the 3 most common etiologies of AKI being pre-renal (27.7%), sepsis-associated (25.5%) and ischemic acute tubular necrosis (15.3%). One hundred and nine (27%) patients received acute renal replacement therapy. In-hospital mortality was 20.3%. Six-month mortality post-AKI event was 9.4%. On survival analysis, patients with KDIGO Stage 3 AKI had significantly shorter survival than other stages.ConclusionAKI is associated with significant in-hospital to 6-month mortality. This signifies the pressing need for AKI prevention, early detection and intervention in mitigating reversible risk factors in order to optimize clinical outcomes.

Capillary Leak Syndrome Following Snakebite Envenomation.

Capillary leak syndrome is a unique complication that follows Russell's viper envenomation. This syndrome has a very high fatality rate and is characterized by parotid swelling, chemosis, periorbital edema, hypotension, albuminuria, hypoalbuminemia, and hemoconcentration. This syndrome is frequently recognized from the southern parts of India, especially from the state of Kerala. It has been postulated that a vascular apoptosis inducing component of Russell's viper venom that is not neutralized by the commercially available anti-snake venom (ASV) is responsible for this complication as it occurs even after adequate doses of ASV administration in most cases. Acute kidney injury often requiring dialysis is invariably present in all patients because of reduced renal perfusion and ischemic acute tubular necrosis as a result of hypotension. Management mainly involves aggressive fluid resuscitation to maintain adequate tissue perfusion. There are no other proven effective treatment modalities, except a few reports of successful treatment with plasmapheresis. Methylprednisolone pulse therapy, terbutaline, aminophylline, and intravenous immunoglobulin are other treatment modalities tried.

NADPH oxidase 4 deficiency increases tubular cell death during acute ischemic reperfusion injury.

NADPH oxidase 4 (NOX4) is highly expressed in kidney proximal tubular cells. NOX4 constitutively produces hydrogen peroxide, which may regulate important pro-survival pathways. Renal ischemia reperfusion injury (IRI) is a classical model mimicking human ischemic acute tubular necrosis. We hypothesized that NOX4 plays a protective role in kidney IRI. In wild type (WT) animals subjected to IRI, NOX4 protein expression increased after 24 hours. NOX4 KO (knock-out) and WT littermates mice were subjected to IRI. NOX4 KO mice displayed decreased renal function and more severe tubular apoptosis, decreased Bcl-2 expression and higher histologic damage scores compared to WT. Activation of NRF2 was decreased in NOX4 KO mice in response to IRI. This was related to decreased KEAP1 oxidation leading to decreased NRF2 stabilization. This resulted in decreased glutathione levels. In vitro silencing of NOX4 in cells showed an enhanced propensity to apoptosis, with reduced expression of NRF2, glutathione content and Bcl-2 expression, similar to cells derived from NOX4 KO mice. Overexpression of a constitutively active form of NRF2 (caNRF2) in NOX4 depleted cells rescued most of this phenotype in cultured cells, implying that NRF2 regulation by ROS issued from NOX4 may play an important role in its anti-apoptotic property.

Serum Lactate Dehydrogenase is Elevated in Ischemic Acute Tubular Necrosis but Not in Acute Rejection in Kidney Transplant Patients.

Serum lactate dehydrogenase (LDH) levels may help to distinguish ischemic acute tubular necrosis (ATN) from acute rejection after kidney transplantation. All kidney biopsies performed in the years 2010 to 2012 were reviewed. Serum LDH, creatinine level, clinical variables, and presence of donor-specific antibodies were recorded before the biopsy. Overall 150 biopsies were included. Ischemic ATN was diagnosed in 45 biopsies and acute cellular-mediated rejection and/or antibody-mediated rejection in 59 biopsies, 38 of which were accompanied by ATN. Serum LDH was elevated in 23 (51%) of 45 cases with ischemic ATN versus 15 (14%) of 105 cases with other diagnoses ( P < .0001). Median serum LDH was 478 U/L (range 277-2018) for ischemic ATN and 372 U/L (range 191-748) for all other diagnoses ( P < .001). When delayed graft function or primary nonfunctioning grafts were caused by ischemic ATN, serum LDH was elevated in 58% of cases, but when caused by acute rejection, LDH was normal in 88% of cases ( P = .02). There is a strong association between elevated serum LDH 1 to 3 days before performing kidney biopsy and the diagnosis of ischemic ATN after kidney transplantation, especially at the immediate posttransplantation period. Normal serum LDH at this period should raise a suspicion of acute rejection.

Microvascular inflammation and acute tubular necrosis are major histologic features of hantavirus nephropathy.

Hantavirus nephropathy (HVN) is an uncommon etiology of acute renal failure due to hantavirus infection. Pathological features suggestive of HVN historically reported are medullary interstitial hemorrhages in a background of acute interstitial nephritis (AIN). However, interstitial hemorrhages may be lacking because of medullary sampling error. This emphasizes that other pathological criteria may be of interest. We performed a retrospective clinicopathological study of 17 serologically proven HVN cases with renal biopsy from 2 nephrology centers in northern France. Histologic analysis was completed by immunohistochemistry with anti-CD3, anti-CD68, and anti-CD34 antibodies. Three control groups were not related to hantavirus infection: acute tubular necrosis (ATN) of ischemic or toxic etiology and AIN were used for comparison. Renal biopsy analysis showed that almost all HVN cases with medullary sampling (9/10) displayed interstitial hemorrhages, whereas focal hemorrhages were detected in 2 of the 7 "cortex-only" specimens. ATN was common, as it was present in 15 (88.2%) of 17 HVN cases. By contrast, interstitial inflammation was scarce with no inflammation or only slight inflammation, representing 15 (88.2%) of 17 cases. Moreover, HVN showed inflammation of renal microvessels with cortical peritubular capillaritis and medullary vasa recta inflammation; peritubular capillaritis was significantly higher in HVN after comparison with ischemic and toxic ATN controls (P = .0001 and P = .003, respectively), but not with AIN controls. Immunohistochemical studies highlighted the involvement of T cells and macrophages in renal microvascular inflammation related to HVN. Our study showed that microvascular inflammation, especially cortical peritubular capillaritis, and ATN are important histologic features of HVN.

Acute kidney injury in patients with human immunodeficiency virus infection.

Acute kidney injury (AKI) is an important cause of hospitalization and morbidity in human immunodeficiency virus (HIV)-positive patients. However, the data on AKI in such patients is limited. The aim of the present study was to analyze the incidence, causes and outcome of AKI in HIV-positive patients from our antiretroviral therapy centre. All HIV-positive patients were evaluated for evidence of clinical AKI. AKI was noted in 138/3540 (3.9%) patients. Of 138 AKI patients, 96 (69.6%) had acquired immuno deficiency syndrome and 42 (30.4%) were HIV seropositive. Majority of AKI patients belonged to AKI network (AKIN) Stage II (42%) or III (48.5%) at presentation. Prerenal, intrinsic and postrenal AKI were noted in 53.6%, 44.2% and 2.2% of cases, respectively. Hypovolemia (44.2%) and sepsis (14.5%) contributed to AKI in vast majority of cases. AKI was multifactorial (volume depletion, sepsis and drugs) in 39% of patients. Acute tubular necrosis (ATN) was the most common intrinsic lesion. Acute interstitial nephritis and diffuse endocapillary proliferative glomerulonephritis were noted in five and two cases, respectively. In-hospital mortality was 24.64%. Lower CD4 count, decreased serum albumin level and Stage 4 WHO disease were associated with higher mortality. At 3 months or more follow-up complete recovery of renal function, chronic kidney disease Stage 3-5 and progression to end stage renal disease were noted in 58.69%, 14.5% and 2.2% of cases, respectively. Thus, prerenal factors and ischemic ATN were the most common cause of AKI in HIV-infected patients. Recovery of renal function was seen in 59% of cases, but AKI had high in-hospital mortality.

Urine interleukin-18 in prediction of acute kidney injury: a systemic review and meta-analysis.

BackgroundInterleukin-18 (IL-18) mediates ischemic acute tubular necrosis; it has been proved as a rapid, reliable, and affordable test marker for the early detection of acute kidney injury (AKI), but its predictive accuracy varies greatly.MethodsMEDLINE and EMBASE, Cochrane Library, Ovid, and Springerlink (from inception to November 15, 2013) were searched for relevant studies (in English) investigating diagnostic accuracy of urine IL-18 to predict AKI in various clinical settings. The text index was increasing or increased urine IL-18 level and the main outcome was the development of AKI, which was primarily based on serum creatinine level [using risk, injury, failure, loss and end-stage renal disease (RIFLE), acute kidney injury network, or modified pediatric RIFLE criteria in pediatric patients]. Pooled estimates of diagnostic odds ratio (OR), sensitivity and specificity were calculated. Summary receiver operating characteristic curves were used to calculate the measures of accuracy and Q point value (Q*). Remarkable heterogeneity was explored further by subgroup analysis based on the different clinical settings.ResultsWe analyzed data from 11 studies of 3 countries covering 2,796 patients. These studies were marked by limitations of threshold and non-threshold effect heterogeneity. Across all settings, the diagnostic OR for urine IL-18 level to predict AKI was 5.11 [95 % confidence interval (CI) 3.22–8.12], with sensitivity and specificity respectively at 0.51 and 0.79. The area under the ROC curve of urine IL-18 level to predict AKI was 0.77 (95 % CI 0.71–0.83). Subgroup analysis showed that urine IL-18 level in pediatric patients (<18 years) and early AKI predictive time (<12 h) were more effective in predicting AKI, with diagnostic ORs of 7.51 (2.99–18.88), 8.18 (2.19–30.51), respectively.ConclusionUrine IL-18 holds promise as a biomarker in the prediction of AKI but has only moderate diagnostic value.

Glomerular haemodynamics, the renal sympathetic nervous system and sepsis-induced acute kidney injury

To describe recent insights into glomerular haemodynamics in septic acute kidney injury (AKI). We reviewed the literature with particular emphasis on recent findings in animal experiments and human studies in relation to renal macro- and micro-renal haemodynamics during septic AKI. The dominant paradigm is that septic AKI is due to decreased renal perfusion with ischaemic loss of glomerular filtration rate (GFR), ischaemic tubular cell injury and acute tubular necrosis (ATN). However, recent experimental and human studies challenge this view of the pathogenesis of septic AKI. In addition, rapid post-mortem and experimental histological studies do not support ATN as the histological substrate of septic AKI. Finally, more recent experimental evidence suggests that changes in the glomerular and peri-glomerular haemodynamics provide a more likely explanation for the loss of GFR seen in the early phases of septic AKI. Despite a long-standing paradigm that septic AKI is due to renal hypo-perfusion and associated ATN, experimental and human studies increasingly suggest that changes in the state of the glomerular and peri-glomerular micro-vasculature are a more likely additional explanation for this condition.

Sustained Activation of EGFR Triggers Renal Fibrogenesis after Acute Kidney Injury

Severe acute kidney injury (AKI) is frequently accompanied by maladaptive repair and renal fibrogenesis; however, the molecular mechanisms that mediate these acute and chronic consequences of AKI remain poorly understood. In this study, we examined the role of epidermal growth factor receptor (EGFR) in these processes using waved-2 (Wa-2) mice, which have reduced EGFR activity, and their wild-type (WT) littermates after renal ischemia. Renal EGFR phosphorylation was induced within 2 days after ischemia, increased over time, and remained elevated at 28 days in WT mice, but this was diminished in Wa-2 mice. At the early stage of postischemia (2 days), Wa-2 mice developed more severe acute renal tubular damage with less reparative responses as indicated by enhanced tubular cell apoptosis, and reduced dedifferentiation and proliferation as compared to WT animals. At the late stage of postischemia (28 days), Wa-2 mice exhibited a less severe renal interstitial fibrosis as shown by reduced activation/proliferation of renal myofibroblasts and decreased deposition of extracellular matrix proteins. EGFR activation also contributed to cell cycle arrest at the G2/M phase, a cellular event associated with production of profibrogenetic factors, in the injured kidney. Collectively, these results indicate that severe AKI results in sustained activation of EGFR, which is required for reparative response of renal tubular cells initially, but eventually leads to fibrogenesis.

Urinary Biomarkers for The Prediction of Reversibility in Acute-on-Chronic Renal Failure

There is no reliable clinical test to predict the reversibility of acute-on-chronic renal failure. We study whether urinary biomarkers could be used as a noninvasive prognostic marker in patients with acute-on-chronic renal failure. We studied 39 adult patients with pre-existing chronic renal impairment presenting to us with acute-on-chronic renal failure. Urinary neutrophil gelatinase-associated lipocalin (NGAL) level was measured. The mRNA of kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), alpha-1-microglobulin (α1M), sodium/hydrogen exchanger-3 (NHE3), beta-2 microglobulin (β2M), and N-acetyl-β-D-glucosaminidase (NAG) in urinary sediment were quantified. Urinary NGAL level significantly correlated with the serum creatinine at presentation (r=0.762, p<0.0001) but not baseline serum creatinine. Urinary sediment β2M expression significantly correlated with baseline glomerular filtration rate (GFR) (r=−0.400, p=0.012). Urinary α1M and NHE3 expressions were significantly higher in ischemic acute tubular necrosis than other causes of acute kidney injury (p<0.0001 and p=0.006, respectively). Urinary α1M expression significantly correlated with the degree of improvement in renal function (r=0.387, p=0.026), as well as the estimated GFR 6 months later (r=0.386, p=0.027). In patients with acute-on-chronic renal failure, urinary NGAL level correlates with the severity of renal failure, while urinary α1M expression correlates with the degree of renal function recovery. Quantification of urinary α1M mRNA may be developed as an non-invasive tool for risk stratification of this group of patients.

Deletion of the epidermal growth factor receptor in renal proximal tubule epithelial cells delays recovery from acute kidney injury

To determine the role of epidermal growth factor receptor (EGFR) activation in renal functional and structural recovery from acute kidney injury (AKI), we generated mice with a specific EGFR deletion in the renal proximal tubule (EGFRptKO). Ischemia–reperfusion injury markedly activated EGFR in control littermate mice; however, this was inhibited in either the knockout or wild-type mice given erlotinib, a specific EGFR tyrosine kinase inhibitor. Blood urea nitrogen and serum creatinine increased to a comparable level in EGFRptKO and control mice 24 h after reperfusion, but the subsequent rate of renal function recovery was markedly slowed in the knockout mice. Twenty-four hours after reperfusion, both the knockout and the inhibitor-treated mice had a similar degree of histologic renal injury as control mice, but at day 6 there was minimal evidence of injury in the control mice while both EGFRptKO and erlotinib-treated mice still had persistent proximal tubule dilation, epithelial simplification, and cast formation. Additionally, renal cell proliferation was delayed due to decreased ERK and Akt signaling. Thus, our studies provide both genetic and pharmacologic evidence that proximal tubule EGFR activation plays an important role in the recovery phase after acute kidney injury.

Evaluation of urine biomarkers of kidney injury in polycystic kidney disease

Progressive disruption of renal tubular integrity in the setting of increased cellular proliferation and apoptosis is a feature of ADPKD. Here we evaluated the effect of these processes on the expression of NGAL and IL-18, markers of tubular injury, in rodent models and in the cyst fluid and urine of patients with ADPKD. Two mouse models where Pkd2 was inactivated which resulted in early or adult onset cysts, were used to evaluate NGAL levels. Further, the Han:SPRD rat model of polycystic disease was used to study IL-18 levels. In four annual serial urine samples from 107 patients with ADPKD in the Consortium for Radiologic Imaging for the Study of Polycystic Kidney Disease (CRISP) study, NGAL and IL-18 excretion rates were determined in conjunction with measures of total kidney volume and estimated GFR (eGFR) by the MDRD equation. Kidneys from affected mice and rats showed prominent expression of NGAL and IL-18/IL-18R, respectively, in epithelial cells lining kidney cysts. In human ADPKD cyst fluid, both NGAL and IL-18 were elevated. In CRISP patients, the mean percentage increase in total kidney volume was 5.4 /year and the mean decline in eGFR 2.4 mL/min/year. The trend of increased mean urine NGAL and IL-18 over three years was statistically significant; however, there was no association of tertiles of IL-18 or quartiles of NGAL and the change in total kidney volume or eGFR over this period. Thus, urinary NGAL and IL-18 excretion are mildly and stably elevated in ADPKD, but do not correlate with changes in total kidney volume or kidney function. This may be due, in part, to the lack of communication between individual cysts and the urinary collecting system in this disorder.

Acute Kidney Injury: Differential Diagnosis and New Biomarker

Incidence of acute kidney injury (AKI) is increasing and despite advances in supportive care, mortality from AKI in critically ill patients still exceeds 50%. Major causes of AKI can be classified into prerenal, renal and postrenal AKI and many of prerenal or ischemic acute tubular necrosis (ATN) are caused by decreased renal blood flow. In addition, exposure to nephrotoxicant or diverse drugs can lead to AKI and diseases that affect larger renal vessels, glomeruli, or renal microvasculature are also other causes of AKI. Because type of renal injury or initiation of proper therapy in setting of AKI is important in determining patient prognosis, differential diagnosis utilizing patients history, physical examination, and laboratory data including urinalysis, urine diagnostic indices, radiologic examination is important. Lack of sensitive biomarkers for early detection of AKI, which resembles troponin in acute myocardial infarction is one critical factor that has hampered the successful translation of various therapeutic strategies that were effective in animal research. However, over the last decade, efforts to identify and validate novel urine or plasma biomarkers in AKI led to identification of several promising biomarkers including neutrophil gelatinase associated lipocalin (NGAL), interleukin-18 (IL-18), cystatin-C and liver type fatty acid binding protein (L-FABP). Although far from replacing serum creatinine in clinical practice yet, data from large clinical studies are promising and here I briefly reviewed the characteristics of them and possible clinical utility in AKI. (Korean J Med 2012;82:5-10)